Eribulin in Male Patients With Breast Cancer: The First Report of Clinical Outcomes.

BACKGROUND: Evidence on the management and treatment of male breast cancer is scant. We report the analysis of a multicenter Italian series of patients with male breast cancer treated with eribulin. To our knowledge, this is the first report on the use or eribulin in this setting. PATIENTS AND METHODS: Patients were retrospectively identified in 19 reference centers. All patients received eribulin treatment, according to the standard practice of each center. Data on the identified patients were collected using a standardized form and were then centrally reviewed by two experienced oncologists. RESULTS: A total of 23 patients (median age, 64 years; range, 42-80) were considered. The median age at the time of diagnosis of breast cancer was 57 years (range, 42-74). HER2 status was negative in 14 patients (61%), and 2 patients (9%) had triple-negative disease. The most common metastatic sites were the lung (n = 14; 61%) and bone (n = 13; 56%). Eribulin was administered for a median of 6 cycles (range, 3-15). All patients reported at least stable disease; two complete responses (9%) were documented. Eribulin was well-tolerated, with only four patients (17%) reporting grade 3 adverse events and two (9%) with treatment interruptions because of toxicity. Eight subjects (35%) did not report any adverse event during treatment. For patients with a reported fatal event, the median overall survival from the diagnosis of metastatic disease was 65 months (range, 22-228). CONCLUSION: Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer. IMPLICATIONS FOR PRACTICE: Evidence on the management and treatment of male breast cancer is eagerly awaited. Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer.

Adjuvant Ovarian Suppression, High-dose Chemotherapy and Immunotherapy for Premenopausal Patients with High-risk Breast Cancer.

BACKGROUND: Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established. PATIENTS AND METHODS: Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity. RESULTS: The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies. CONCLUSION: Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients.

Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer.

The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS.

Vascular endothelial growth factor expression and T-regulatory cells in premenopausal breast cancer.

Estradiol (E2) plays a key role in human reproduction through the induction of vascular endothelial growth factor (VEGF) and T-regulatory cells (T-Regs), which are also important in breast cancer (BC) growth. The primary endpoint of the present study was the investigation of whether E2 suppression, chemotherapy and radiation therapy decreased the levels of VEGF and T-Regs of premenopausal patients with high-risk early BC. The secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Between April 2003 and July 2008, 100 premenopausal women with early, high-risk BC were entered into the study. The characteristics of the patients were as follows: median age, 43 years (range, 26-45); median number of positive axillary nodes, 3.3; median Ki-67, 33%. Plasma E2, VEGF and T-Reg were measured at baseline and every year. Treatment comprised luteneizing hormone-releasing hormone (LH-RH) analogue, tailored chemotherapy, radiation therapy and hormonal therapy in oestrogen receptor-positive (ER+) tumours. At 4 years, a statistically significant decrease in E2, VEGF and T-Reg levels was observed; the PFS and OS rates were 94 and 98%, respectively. Hot flushes and G1 osteopenia occurred following LH-RH analogue administration, while no unexpected toxicity was observed following chemotherapy. E2 deprivation with an LH-RH analogue, tailored chemotherapy, radiation therapy and hormonal therapy in ER+ tumours decreased plasma VEGF levels and T-Regs numbers in premenopausal high-risk ER+ and ER- BC patients. In addition, a favorable impact on PFS and OS was observed.

Chemoembolization of unresectable hepatocellular carcinoma: Decreased toxicity with slow-release doxorubicin­eluting beads compared with lipiodol.

Chemoembolization with lipiodol (TACE) improves survival of selected patients with unresectable hepatocellular carcinoma (HCC), but results in substantial toxicity. To improve treatment tolerance, we conducted this phase II study using doxorubicin-loaded beads (DC Beads®) delivered by selective transcatheter arterial chemoembolization (DEB-TACE). We compared the results with those obtained with TACE in our historical controls. Thirty-five patients were recruited with diagnoses of HCC. Patients received DEB-TACE with doxorubicin loaded on DC Beads. Computed tomography of the upper abdomen was performed one month after DEB-TACE. Historical controls were a group of 70 patients with matched characteristics treated with TACE. After a median follow-up of 14.1 months (range, 6-36 months), 22 patients (63%) had an objective response. There was a statistically significant decrease in liver enzymes (p<0.001), lactate dehydrogenase, (p<0.001) in DEB-TACE-treated patients compared to TACE-treated patients. DEB-TACE with doxorubicin-loaded DC Beads, a safe and reliable treatment for HCC, leads to decreased toxicity compared to TACE.

Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study.

Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile.

Premenopausal hormone-responsive breast cancer with extensive axillary nodes involvement: total estrogen blockade and chemotherapy.

BACKGROUND: Poor prognosis is associated with estrogen- and/or progesterone receptor-positive (ER(+), PGR(+)) premenopausal breast cancer (PM-BC) with high Ki-67 labeling index and extensive axillary lymph node involvement. The role of adjuvant chemotherapy (CT) and hormonal therapy have not yet been established in these patients. PATIENTS AND METHODS: Twenty-five PM-BC patients received, in sequence, leuprorelin, taxane-anthracycline induction chemotherapy, radiation therapy, a platinum-based intensification high-dose CT, followed by leuprorelin and anastrazole for five years. Vascular endothelial growth factor (VEGF) levels were measured as the primary end-point; secondary end-points were 10-year relapse-free survival (RFS) and overall survival (OS) rates. RESULTS: The median patient age was 44 years, and the mean number of positive axillary nodes was 14. All patients were ER(+) and/or PGR(+), with a median Ki-67 index of 33%. Five patients were Cerb-B2 positive. Grade 4 hematologic toxicity was observed in all patients, no patient showed a decrease of cardiac ejection fraction and hot flashes and arthralgias were of moderate intensity. After a median follow-up of 70 months, VEGF levels significantly decreased (p<0.001); 10-year RFS and OS were 76% and 78%, respectively. CONCLUSION: Total estrogen blockade and high-dose CT in PM-BC patients is feasible, has moderate toxicity, significantly reduces VEGF levels, and seems to improve the expected RFS and OS.

Liposomal pegylated doxorubicin and oxaliplatin as salvage chemotherapy in patients with metastatic gastric cancer treated earlier.

The aim of this study was to evaluate the activity and safety of pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) as salvage chemotherapy in patients with metastatic gastric cancer (MGC) who had earlier been treated with docetaxel, capecitabine, 5-fluorouracil, and leucovorin. Treatment consisted of PLD (40 mg/m(2)) and LOHP (120 mg/m(2)) administered over 2 days, every 3 weeks. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors; toxicity was evaluated by the National Cancer Institute common toxicity criteria (version 2.0). Thirty-six patients with pretreated MGC and a mean age of 66 years were recruited for the study. After a median follow-up of 11 months and 202 courses of chemotherapy administered (median, five courses per patient), the overall response rate in the 36 evaluable patients was estimated to be 28%. Grades 3 and 4 hematological toxicities were neutropenia in 44% of patients, grade 2-3 diarrhea in 14% of patients, and grade 2 neuropathy in 12 patients. Median progression-free survival and overall survival were 5.8 and 9.2 months, respectively, with 1-year survival rate of 36%, [95% confidence interval (CI): 21-54%]. Median survival time from the diagnosis of metastatic disease was 31.5 months. Seventy-two percent of patients (n=26) (95% CI: 58-88%) obtained a clinical benefit from this chemotherapy regimen. PLD and LOHP is an active regimen, able to give palliation in a substantial percentage of MCG patients who have been pretreated with taxanes.

Prolonged disease control after myeloablative chemotherapy, autologous transplantation and immunotherapy in high-risk early breast cancer.

BACKGROUND: Failure to eradicate all cancer stem cells, lymphocytopenia, and high levels of vascular endothelial growth factor (VEGF) may explain the limited efficacy of high dose-chemotherapy (HDCT) with peripheral progenitor cell transplantation (PBPCT) in high-risk early breast cancer with more than 10 axillary nodes (HRBC). PATIENTS AND METHODS: With the aim of increasing patient's lymphocyte count and reducing VEGF, wich could translate into an improved immune function and a better clinical outcome, patients with HRBC, received HDCT, PBPCT and immunotherapy with interleukin-2 (IL-2) and 13-cis retinoic acid (RA). RESULTS: A total of 30 HRBC patients were entered into the study. Grade 4 hematological toxicity was universal, while major adverse effects of IL-2 were fever, rash and autoimmune reactions. After a median follow-up of 61 months, immune function improved with a statistically significant increase of lymphocyte count and a decrease in VEGF levels. This translated into an unexpected 5-year relapse-free and overall survival rates of 76% and 85%, respectively. CONCLUSION: These data show that IL-2 and RA administration after HDCT and PBPCT is feasible and, as well as giving a statistically significant improvement in lymphocyte count and a decrease of VEGF, also seems to improve the expected clinical outcome.

Maintenance immunotherapy in recurrent ovarian cancer: long term follow-up of a phase II study.

OBJECTIVES: Vascular endothelial growth factor (VEGF), a mediator of tumor-associated immunodeficiency, plays a key role in angiogenesis and is a prognostic factor in advanced ovarian cancer (AOC). Previously, we showed that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) improved the tumor-associated immunodeficiency and decreased VEGF in patients with AOC. Here, we report long term follow-up of a group of patients with platinum-sensitive AOC who were treated with IL-2 and RA. METHODS: Sixty-five patients with AOC who had a clinical benefit from second line chemotherapy and elevated serum levels of VEGF were entered into the study from 04/98 to 04/05. Therapy consisted of low-dose subcutaneous IL-2 and oral RA, administered on intermittent schedules for up to 5 years. RESULTS: A statistically significant improvement in lymphocyte and NK counts and a decrease in VEGF levels were observed with respect to baseline values among the 65 evaluable patients. Five-year progression-free survival and overall survival rate were 29% and 38%, respectively. CONCLUSIONS: These data show that patients treated with low-dose IL-2 and RA have a statistically significant improvement in their lymphocyte and NK counts, a decrease in VEGF, and seem to have an improved clinical outcome.

High-risk early breast cancer in patients under 40 years of age: Improved clinical outcome with total estrogen blockade and tailored chemotherapy.

This multicenter prospective trial assessed the outcome in 63 patients, 40 years of age or younger, with high-risk early breast cancer (HREBC), included in an ovarian protection study. The patients were treated with a luteinizing hormone-releasing hormone (LH-RH) analogue administered for 5 years, tailored chemotherapy and an aromatase inhibitor, in estrogen receptor-positive (ER(+)) patients. T-regulatory cells (T-regs) and vascular endothelial growth factor (VEGF) were measured at baseline and yearly. The mean age of the patients was 36 years (range 26-40). Sixty-five percent had ER(+) tumors, 24% had negative axillary nodes with tumors >1 cm and high histological grade with lymphovascular invasion, while 76% had a mean of 3.6 positive axillary nodes (range 1-21). Serum estradiol was maintained at values <40 pg/ml in all of the patients. A statistically significant decrease in VEGF (P<0.0001) and T-regs (P<0.0001), with respect to baseline values, was observed after LH-RH administration. After a median follow-up of 110 months, the 10-year progression-free and overall survival rates were 86.1 and 89.7%, respectively. These data revealed that the administration of an LH-RH analogue to HREBC patients, followed by chemotherapy and hormonal therapy, decreased VEGF and T-regs and improved the expected clinical outcome.

Chemoradioimmunotherapy in locally advanced pancreatic and biliary tree adenocarcinoma: a multicenter phase II study.

OBJECTIVES: The antitumor activity and toxicity of a multi-step treatment were evaluated in patients with locally advanced, inoperable, or incompletely resected pancreatic (Pa) and biliary tree (Bt) adenocarcinomas (ADKs). METHODS: Fifty-four patients, 63% with Pa and 37% with Bt ADK, received 3 courses of cisplatin-gemcitabine induction chemotherapy. Progression-free (PF) patients were given consolidation radiotherapy with concurrent capecitabine. PF patients had, as maintenance immunotherapy (MI), interleukin 2 (1.8x10 IU) and 13-cis-retinoic acid (0.5 mg/kg) [DOSAGE ERROR CORRECTED]. RESULTS: Thirty-eight patients, 27 with Pa and 11 with Bt ADKs, PF after cisplatin/gemcitabine, were treated with consolidation radiotherapy with concurrent capecitabine. Fourteen PF patients, 7 with Pa and 7 with Bt ADK, received MI. Median PF and overall survivals (OS) for all 54 patients were 6.8 and 12.1 months, respectively. Patients treated with MI had a median PF survival of 16.2 months, whereas median OS had not been reached yet, after a median follow-up of 27.5 months. TOXICITY: Grades 3 and 4 hematological and gastrointestinal in 30% and 37% of patients, respectively; grades 1 and 2 autoimmune reactions in 28% of patients. CONCLUSIONS: These results support the efficacy and safety of a multi-step sequential treatment in patients with locally advanced, inoperable or incompletely resected Pa and Bt ADKs.

Immunotherapy in patients with less than complete response to chemotherapy.

BACKGROUND: Patients with metastatic solid tumors (MST) with less than a complete response to chemotherapy (L-CR), a depressed immune system and elevated serum vascular endothelial growth factor (VEGF) lack defined treatment options. The primary endpoint evaluated in this study was whether interleukin-2 (IL-2) and 13-cisretinoic acid (RA) treatment reduced VEGF and improved immune function in such patients. Secondary endpoints were objective response, relapse-free survival (RFS), and overall survival (OS). PATIENTS AND METHODS: One hundred consecutive MST patients with L-CR and a mean serum VEGF of 421.0 pg/mm3 were enrolled. Patients self-administered subcutaneous IL-2 1.8 x 10(6) IU/day, and oral RA 0.5 mg/kg/day x 5 days/week for 2 cycles of 3 weeks/month for 1 year and continued until progression. RESULTS: After a median follow-up of 78 months, a statistically significant VEGF decrease and improvements in lymphocyte, NK, and CD4+/CD8+ ratio were observed. Twenty-four patients were converted to a CR; their 5-year RFS and OS rates were each 96%. No WHO grade 3 or 4 toxicities were observed. CONCLUSION: Administration of IL-2/RA to this patient population produced a significant decrease in VEGF, improvement of prognostically relevant immunological parameters, and durable response in 25% of patients.

Beta-interferon, retinoids and tamoxifen in metastatic breast cancer: long-term follow-up of a phase II study.

Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of beta-interferon (beta-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, beta-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, beta-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

Maintenance immunotherapy in metastatic breast cancer.

Maintenance chemotherapy provides only a modest survival advantage in metastatic breast cancer (MBC). We have previously shown that a maintenance immunotherapy (MI) regimen based on low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) improved the lymphocyte and natural killer cell (NK) counts, and CD4+/CD8+ ratio in patients with a clinical benefit from chemotherapy. With the aim of improving progression-free survival (PFS), 100 consecutive MBC patients with a clinical benefit from chemotherapy were treated with an MI. Patients with MBC were eligible if they had no evidence of progression after 6-8 courses of epirubicin-paclitaxel induction chemotherapy. Treatment consisted of low-dose IL-2 and oral RA given until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS), and changes in immunological parameters. From 04/1997 to 04/2002, 100 patients with MBC were enrolled. After a median follow-up of 49 months, median PFS and OS were 37.1 and 57.5 months, respectively. No WHO grade 3 or 4 toxicity was observed; grade 2 cutaneous toxicity and autoimmune reactions occurred in 19 and 16% of patients, respectively. A sustained improvement in lymphocytes, NKs, and in the CD4+/CD8+ ratio was observed, with respect to baseline values. In conclusion, MI with IL-2 and RA in MBC patients who do not progress after 6-8 courses of chemotherapy is well-tolerated, improves lymphocyte, NK, CD4+/CD8+ ratio, and appears to delay disease recurrence. A randomized trial is warranted.

Alternating XELFOX and XELFIRI in patients with metastatic colorectal cancer.

BACKGROUND: To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer. MATERIALS AND METHODS: The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2). RESULTS: All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients. CONCLUSIONS: The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

Maintenance immunotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck.

The purpose of this study was to determine the efficacy and safety of a maintenance immunotherapy regimen administered to patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RMHN) who showed clinical benefit from docetaxel, ifosfamide, and cisplatin chemotherapy (DIP). Every 4 weeks, patients with RMHN received 60 mg/m docetaxel on day 1, and 1200 mg/m ifosfamide and 20 mg/m cisplatin on days 1 to 4. Low-dose subcutaneous interleukin-2 and oral 13-cis-retinoic acid were administered as maintenance immunotherapy to patients who showed a clinical benefit (complete or partial response, disease stability). The primary end point was response; secondary end points were progression-free survival, overall survival, toxicity, and evaluations of lymphocytes, natural killer cells, and serum vascular endothelial growth factor (VEGF). After a median follow-up of 22 months, 263 courses of chemotherapy were administered to the 54 patients. The overall response rate was 59%. Forty-two patients (78%) had a clinical benefit and received 185 courses of maintenance immunotherapy. Median progression-free survival and overall survival were 11.1 and 21.8 months, respectively. Statistically significant, progressive increases in lymphocytes and natural killer cells and a decrease in VEGF were observed in patients treated with maintenance immunotherapy. The toxicity was relatively well tolerated and caused no death. Outpatient administration of DIP, followed by low-dose interleukin-2 and 13-cis-retinoic acid, was generally well tolerated and showed promising activity against RMHN. Longitudinal changes in lymphocytes, natural killer cells, and VEGF might be useful biomarkers for response and survival.

Multicenter phase II study of chemoimmunotherapy in the treatment of metastatic melanoma.

Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.

A multicenter phase II study of pegylated liposomal doxorubicin and oxaliplatin in recurrent ovarian cancer.

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) are active as single agents in the treatment of recurrent ovarian cancer (ROC). This phase II study investigated the safety and activity of PLD and LOHP used in combination to treat ROC. METHODS: Eligibility criteria included disease recurrence after one (45%) or more lines (55%) of chemotherapy, performance status 3 months. Treatment was 40 mg/m(2) PLD and 120 mg/m(2) LOHP, administered over 2 days, every 3 weeks. Response to therapy was assessed using the RECIST criteria. RESULTS: Forty patients with ROC enrolled in the study from 10/2001 to 10/2005; 27 patients were platinum-sensitive and 13 were platinum-resistant. Major toxicities included grade 3-4 neutropenia (37%) and grade 2 palmar-plantar erythrodysesthesia (10%). The overall response rate was 67.5%, with 30% stable disease rate and 2.5% progressive disease rate. The median progression-free survival (PFS) was 9.6 months, while median overall survival was 18.3 months, with no statistically significant difference in PFS between platinum-resistant and platinum-sensitive patients. CONCLUSION: We conclude that the combination of PLD and LOHP shows activity in ROC with a manageable toxicity profile and can be safely administered in heavily pre-treated patients.

Chemoimmunotherapy in the treatment of metastatic gastric cancer.

Docetaxel, capecitabine and 5-fluorouracil have been shown to be active in the treatment of metastatic gastric adenocarcinoma. Consistent with this finding, the aim of this study was to test this combination in a clinical trial. Forty-one patients with metastatic gastric adenocarcinoma and a median age of 64 years were recruited for the study. The treatment was based on the administration of docetaxel 60 mg/m2 every 4 weeks, leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and capecitabine 1000 mg/m2 twice daily on days 1 and 2 every 2 weeks. Patients achieving a clinical benefit were treated, as maintenance immunotherapy, with low-dose interleukin-2 and 13-cis-retinoic acid. The primary end point of this phase II study was the response rate. The secondary end points relied on the evaluation of the immunological parameters, toxicity, and progression-free survival and overall survival. The overall response rate in the 41 evaluable patients was estimated to be 49%. Median progression-free and overall survival was 9.5 and 21.1 months, respectively. Grade 3 and 4 hematological toxicities were neutropenia and thrombocytopenia in 44 and 5% of patients, respectively. A sustained improvement of evaluated immunological parameters with a negligible toxicity profile was observed in the 27 patients treated with interleukin 1-2/13-cis-retinoic acid. Docetaxel in combination with leucovorin, 5-fluorouracil and capecitabine followed by low-dose interleukin 1-2 and 13-cis-retinoic acid is well tolerated, and shows a significant activity in patients with metastatic gastric adenocarcinoma.